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2-Mercaptomethylbenzo[d]imidazole (2-MMBI) derivatives were designed and synthesized as tyrosinase (TYR) chelators using 2-mercaptomethylimidazole scaffolds. Seven of the ten 2-MMBI derivatives exhibited stronger inhibition of mushroom TYR activity than kojic acid. Their ability to chelate copper ions was demonstrated through experiments using the copper chelator pyrocatechol violet and assays measuring TYR activity in the presence or absence of exogenous CuSO4. The inhibition mechanisms of derivatives 1, 3, 8, and 9, which showed excellent TYR inhibitory activity, were elucidated through kinetic studies and supported by the docking simulation results. Derivatives 3, 7, 8, and 10 significantly inhibited cellular TYR activity and melanin production in B16F10 cells in a dose-dependent manner, with stronger potency than kojic acid. Furthermore, in situ, derivatives 7 and 10 showed stronger inhibitory effects on B16F10 cell TYR activity than kojic acid. Six derivatives, including 8, showed highly potent depigmentation in zebrafish larvae, outpacing kojic acid even at 200–670 times lower concentrations. Additionally, all derivatives could scavenge for reactive oxygen species without causing cytotoxicity in epidermal cells. These results suggested that 2-MMBI derivatives are promising anti-melanogenic agents. [ABSTRACT FROM AUTHOR]

8-Prenylgenistein (8PG), a genistein derivative, is present in fermented soybeans (Glycine max), including cheonggukjang (CGJ), and exhibits osteoprotective, osteogenic, and antiadipogenic properties. However, the hepatoprotective effects of 8PG and its underlying molecular mechanisms remain largely unexplored. Here, we identified the high binding affinity of 8PG with AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1), which acts as a potent AMPK activator that counteracts hepatic steatosis. Notably, 8PG exhibited better pharmacokinetics with greater absorption and higher plasma binding than the positive controls for the target proteins. Moreover, 8PG exerted non-carcinogenic activity in rats and significantly increased AMPK phosphorylation. Compound C, an AMPK inhibitor, did not antagonize 8PG-activated AMPK in HepG2 cells. 8PG significantly attenuated palmitate-induced lipid accumulation and enhanced phosphorylated AMPK and its downstream target, acetyl-CoA carboxylase. Further, 8PG activated nuclear SIRT1 at the protein level, which promoted fatty acid oxidation in palmitate-treated HepG2 cells. Overall, 8PG acts as a potent AMPK activator, further attenuating hepatic steatosis via the SIRT1-mediated pathway and providing new avenues for dietary interventions to treat metabolic dysfunction-associated steatotic liver disease (MASLD). [ABSTRACT FROM AUTHOR]

Inspired by the potent tyrosinase inhibitory activity of phenolic compounds with a 2-phenylbenzo[d]thiazole scaffold, we explored phenolic compounds 1–15 with 2-phenylbenzo[d]oxazole, which is isosterically related to 2-phenylbenzo[d]thiazole, as novel tyrosinase inhibitors. Among these, compounds 3, 8, and 13, featuring a resorcinol structure, exhibited significantly stronger mushroom tyrosinase inhibition than kojic acid, with compound 3 showing a nanomolar IC50 value of 0.51 μM. These results suggest that resorcinol plays an important role in tyrosinase inhibition. Kinetic studies using Lineweaver–Burk plots demonstrated the inhibition mechanisms of compounds 3, 8, and 13, while docking simulation results indicated that the resorcinol structure contributed to tyrosinase binding through hydrophobic and hydrogen bonding interactions. Additionally, these compounds effectively inhibited tyrosinase activity and melanin production in B16F10 cells and inhibited B16F10 tyrosinase activity in situ in a concentration-dependent manner. As these compounds showed no cytotoxicity to epidermal cells, melanocytes, or keratinocytes, they are appropriate for skin applications. Compounds 8 and 13 demonstrated substantially higher depigmentation effects on zebrafish larvae than kojic acid, even at 800- and 400-times lower concentrations than kojic acid, respectively. These findings suggest that 2-phenylbenzo[d]oxazole is a promising candidate for tyrosinase inhibition. [ABSTRACT FROM AUTHOR]

Based on the fact that substances with a β-phenyl-α,β-unsaturated carbonyl (PUSC) motif confer strong tyrosinase inhibitory activity, benzylidene-3-methyl-2-thioxothiazolidin-4-one (BMTTZD) analogs 1–8 were prepared as potential tyrosinase inhibitors. Four analogs (1–3 and 5) inhibited mushroom tyrosinase strongly. Especially, analog 3 showed an inhibitory effect that was 220 and 22 times more powerful than kojic acid in the presence of l-tyrosine and l-dopa, respectively. A kinetic study utilizing mushroom tyrosinase showed that analogs 1 and 3 competitively inhibited tyrosinase, whereas analogs 2 and 5 inhibited tyrosinase in a mixed manner. A docking simulation study indicated that analogs 2 and 5 could bind to both the tyrosinase active and allosteric sites with high binding affinities. In cell-based experiments using B16F10 cells, analogs 1, 3, and 5 effectively inhibited melanin production; their anti-melanogenic effects were attributed to their ability to inhibit intracellular tyrosinase activity. Moreover, analogs 1, 3, and 5 inhibited in situ B16F10 cellular tyrosinase activity. In three antioxidant experiments, analogs 2 and 3 exhibited strong antioxidant efficacy, similar to that of the positive controls. These results suggest that the BMTTZD analogs are promising tyrosinase inhibitors for the treatment of hyperpigmentation-related disorders. [ABSTRACT FROM AUTHOR]

Ten 2-mercaptobenzimidazole (2-MBI) analogs were synthesized as potential tyrosinase inhibitors because mercapto-containing compounds can bind to copper ions at the active site of tyrosinase to inhibit enzyme activity. Nine 2-MBI analogs showed sub-micromolar IC50 values for mushroom tyrosinase monophenolase activity; analog 4 was 280-fold more potent than kojic acid, and in diphenolase activity, 6 was 970-fold more potent than kojic acid. The inhibition mode of the 2-MBI analogs was investigated using kinetic studies supported by docking simulations. Benzimidazoles without the 2-mercapto substituent of the 2-MBI analogs lost their tyrosinase inhibitory activity, implying that the 2-mercapto substituent plays an important role in tyrosinase inhibition. The 2-MBI analogs exerted potent antioxidant effects against 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS), 2,2-diphenyl-1-picrylhydrazyl (DPPH), and reactive oxygen species (ROS). The results obtained from apple slices and human embryonic kidney cells (HEK-293) suggest that most 2-MBI analogs are sufficiently safe candidates to delay the browning of apple slices effectively. Thus, these results support the potential use of 2-MBI analogs as anti-browning agents in foods such as mushrooms, vegetables, and fruits. [ABSTRACT FROM AUTHOR]

(Z)-5-Benzylidene-2-phenylthiazol-4(5H)-one ((Z)-BPT) derivatives were designed by combining the structural characteristics of two tyrosinase inhibitors. The double-bond geometry of trisubstituted alkenes, (Z)-BPTs 1–14, was determined based on the 3JC,Hβ coupling constant of 1H-coupled 13C NMR spectra. Three (Z)-BPT derivatives (1–3) showed stronger tyrosinase inhibitory activities than kojic acid; in particular, 2 was to be 189-fold more potent than kojic acid. Kinetic analysis using mushroom tyrosinase indicated that 1 and 2 were competitive inhibitors, whereas 3 was a mixed-type inhibitor. The in silico results revealed that 1–3 could strongly bind to the active sites of mushroom and human tyrosinases, supporting the kinetic results. Derivatives 1 and 2 decreased the intracellular melanin contents in a concentration-dependent manner in B16F10 cells, and their anti-melanogenic efficacy exceeded that of kojic acid. The anti-tyrosinase activity of 1 and 2 in B16F10 cells was similar to their anti-melanogenic effects, suggesting that their anti-melanogenic effects were primarily owing to their anti-tyrosinase activity. Western blotting of B16F10 cells revealed that the derivatives 1 and 2 inhibited tyrosinase expression, which partially contributes to their anti-melanogenic ability. Several derivatives, including 2 and 3, exhibited potent antioxidant activities against ABTS cation radicals, DPPH radicals, ROS, and peroxynitrite. These results suggest that (Z)-BPT derivatives 1 and 2 have promising potential as novel anti-melanogenic agents. [ABSTRACT FROM AUTHOR]

In this study, (Z)-2-(benzylamino)-5-benzylidenethiazol-4(5H)-one (BABT) derivatives were designed as tyrosinase inhibitors based on the structure of MHY2081, using a simplified approach. Of the 14 BABT derivatives synthesized, two derivatives ((Z)-2-(benzylamino)-5-(3-hydroxy-4-methoxybenzylidene)thiazol-4(5H)-one [7] and (Z)-2-(benzylamino)-5-(2,4-dihydroxybenzylidene)thiazol-4(5H)-one [8]) showed more potent mushroom tyrosinase inhibitory activities than kojic acid, regardless of the substrate used; in particular, compound 8 was 106-fold more potent than kojic acid when l-tyrosine was used as the substrate. Analysis of Lineweaver–Burk plots for 7 and 8 indicated that they were competitive inhibitors, which was confirmed via in silico docking. In experiments using B16F10 cells, 8 exerted a greater ability to inhibit melanin production than kojic acid, and it inhibited cellular tyrosinase activity in a concentration-dependent manner, indicating that the anti-melanogenic effect of 8 is attributable to its ability to inhibit tyrosinase. In addition, 8 exhibited strong antioxidant activity to scavenge 2,2-diphenyl-1-picrylhydrazyl and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radicals and peroxynitrite and inhibited the expression of melanogenesis-associated proteins (tyrosinase and microphthalmia-associated transcription factor). These results suggest that BABT derivative 8 is a promising candidate for the treatment of hyperpigmentation-related diseases, owing to its inhibition of melanogenesis-associated protein expression, direct tyrosinase inhibition, and antioxidant activity. [ABSTRACT FROM AUTHOR]

Sixteen compounds bearing a benzothiazole moiety were synthesized as potential tyrosinase inhibitors and evaluated for mushroom tyrosinase inhibitory activity. The compound 4-(5-(trifluoromethyl)benzo[d]thiazol-2-yl)benzene-1,3-diol (compound 1b) exhibited the highest tyrosinase activity inhibition, with an IC50 value of 0.2 ± 0.01 μM (a potency 55-fold greater than kojic acid). In silico results using mushroom tyrosinase and human tyrosinase showed that the 2,4-hydroxyl substituents on the phenyl ring of 1b played an important role in the inhibition of both tyrosinases. Kinetic studies on mushroom tyrosinase indicated that 1b is a competitive inhibitor of monophenolase and diphenolase, and this was supported by docking results. In B16F10 murine melanoma cells, 1a and 1b dose-dependently and significantly inhibited melanin production intracellularly, and melanin release into medium more strongly than kojic acid, and these effects were attributed to the inhibition of cellular tyrosinase. Furthermore, the inhibition of melanin production by 1b was found to be partially due to the inhibition of tyrosinase glycosylation and the suppression of melanogenesis-associated genes. Compound 1c, which has a catechol group, exhibited potent antioxidant activities against ROS, DPPH, and ABTS, and 1b also had strong ROS and ABTS radical scavenging activities. These results suggest that 5-(trifluoromethyl)benzothiazole derivatives are promising anti-tyrosinase lead compounds with potent antioxidant effects. [ABSTRACT FROM AUTHOR]